Labelled fibrinogen receptor antagonists, the use thereof and processes for preparing them

- Dr. Karl Thomae, GmbH

The invention relates to new labelled fibrinogen receptor antagonists which have an affinity for the receptor which is comparable to or greater than that of .sup.125 I-fibrinogen and whose binding is not disrupted by foreign proteins.

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Claims

1. A method of testing binding capability of a chemical substance to fibrinogen receptors which comprises combining a chemical substance to be tested with an amidine of formula

R.sub.a represents a 4-amidinophenyl group, and
R.sub.b represents an HOOC--D--C--B--A-- group, wherein
A represents an optionally methoxy-substituted phenylene group,
B represents a methyleneoxy group bound to the group A via the oxygen atom,
C represents a pyrrolidin-di-yl or pyrrolidinon-di-yl group substituted by the group R.sub.3 at the nitrogen atom, and
D represents a bond or a methylene or ethylene group, whilst
R.sub.3 represents a hydrogen atom, a 3-phenylpropyl, acetyl, methanesulphonyl or pyrrolidinocarbonylmethyl group,

2. An amidine of formula

R.sub.a represents a 4-amidinophenyl group, and
R.sub.b represents an HOOC--D--C--B--A-- group, wherein
A represents an optionally methoxy-substituted phenylene group,
B represents a methyleneoxy group bound to the group A via the oxygen atom,
C represents a pyrrolidin-di-yl or pyrrolidinon-di-yl group substituted by the group R.sub.3 at the nitrogen atom, and
D represents a bond or a methylene or ethylene group, whilst
R.sub.3 represents a hydrogen atom, a 3-phenylpropyl, acetyl, methanesulphonyl or pyrrolidinocarbonylmethyl group,

3. The fibrinogen receptor antagonist as recited in claim 2,

R.sub.a represents a 4-amidino-phenyl group,
R.sub.b represents a phenyl group which is substituted in the 4-position by a 4-carboxymethyl-pyrrolidin-2-yl-methyloxy or 3-carboxymethyl-pyrrolidin-2-on-5-yl-methyloxy group, whilst in the 1-position each pyrrolidine moiety may be substituted by an acetyl or methanesulphonyl group and the pyrrolidinone moiety may be substituted by a 3-phenyl-propyl or pyrrolidinocarbonylmethyl group,

4. The fibrinogen receptor antagonist as recited in claim 2, further characterized in that an aromatic hydrogen atom is replaced by tritium.

9. A method for determining concentration of fibrinogen antagonists in a mixture of various chemical substances which comprises mixing a tritium labeled amidine of formula

R.sub.a represents a 4-amidinophenyl group, and
R.sub.b represents an HOOC--D--C--B--A-- group, wherein
A represents an optionally methoxy-substituted phenylene group,
B represents a methyleneoxy group bound to the group A via the oxygen atom,
C represents a pyrrolidin-di-yl or pyrrolidinon-di-yl group substituted by the group R.sub.3 at the nitrogen atom, and
D represents a bond or a methylene or ethylene group, whilst
R.sub.3 represents a hydrogen atom, a 3-phenylpropyl, acetyl, methanesulphonyl or pyrrolidinocarbonylmethyl group,

10. The method of claim 9 wherein the mixture comprises albumin or other body fluids.

Referenced Cited
U.S. Patent Documents
5455348 October 3, 1995 Austel et al.
5463071 October 31, 1995 Himmelsbach et al.
5478942 December 26, 1995 Himmelsbach et al.
Foreign Patent Documents
0372486 December 1989 EPX
0381033 January 1990 EPX
0503548 March 1992 EPX
0483667 May 1992 EPX
0496378 July 1992 EPX
0525629 July 1992 EPX
0528369 February 1993 EPX
0381033 August 1993 EPX
4129603 September 1991 DEX
4134467 October 1991 DEX
Other references
  • "Low Molecular Weight, non-Peptide Fibrinogen Receptor Antagonists" J. Med. Chem. May 4, 1992, 35, 4393-4407.
Patent History
Patent number: 5677466
Type: Grant
Filed: May 23, 1995
Date of Patent: Oct 14, 1997
Assignee: Dr. Karl Thomae, GmbH (Biberach an der Riss)
Inventors: Johannes Weisenberger (Biberach), Hans-Dieter Schubert (Biberach), Gunter Linz (Mittelbiberach), Karl-Heinz Switek (Biberach), Frank Himmelsbach (Mittelbiberach)
Primary Examiner: Matthew V. Grumbling
Attorneys: R. P. Raymond, A. R. Stempel, M-E. M. Devlin
Application Number: 8/477,667